Chemical structure

Related Biological Data

Biological Activity

VX-765 is a novel Caspase-1 inhibitor being investigated for the treatment of epilepsy, currently being developed by Vertex.

Targets

Caspase-1

IC50

Protocol

Kinase experiment [1]:

Protease enzyme assays

Enzyme inhibition was assayed by tracking of the rate of hydrolysis of an appropriate substrate labeled with either p-nitroaniline or aminomethyl coumarin (AMC) as follows: ICE/caspase-1, suc-YVAD-p-nitroanilide; caspase-4, Ac-WEHD-AMC; caspase-6, Ac-VEID-AMC; caspase-3, -7, -8, and -9, Ac-DEVD-AMC; and granzyme B, Ac-IEPD-AMC. Enzymes and substrates were incubated in a reaction buffer [10 mM Tris, pH 7.5, 0.1% (w/v) CHAPS, 1 mM dithiothreitol, and 5% (v/v) dimethyl sulfoxide] for 10 mins at 37 °C. Glycerol was added to the buffer at 8% (v/v) for caspase-3, -6, and -9 and granzyme B to improve stability of enzymes. The rate of substrate hydrolysis was monitored using a fluorometer.

Animal experiment [1]:

Animal models

Collagen-induced arthritis (CIA) mouse model

Dosage form

10, 25, 50 or 100 mg/kg; p.o.; b.i.d.; for 24 days.

Applications

In a CIA mouse model, VX-765 significantly reduced the inflammation scores in a dose-dependent manner. In addition, 100 mg/kg VX-765 was as efficacious as 5 mg/kg Prednisolone.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

Evaluation sample solution : ship with blue ice.All other available size: ship with RT , or blue ice upon request

General tips

For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.

Background

VX-765, an orally- absorbed pro-drug of VRT-043198, is a potent and selective inhibitor of caspase-1 which belongs to the ICE/caspase-1 sub-family caspases.

Caspase-1, known as interleukin (IL)-1-converting enzyme, is responsible for the processing of a key inflammatory mediator IL-1β from an in active precursor to an active, secreted protein. In response to intracellular bacteria, caspase-1 is also reported to be involved in a rapid programme of cell death, termed pyroptosis in macrophages [1].

VX-765 is usually metabolized to an active molecular VRT-043198. In cultures of peripheral blood mononuclear cells stimulated with bacterial products, VRT-043198 inhibited the release of Interleukin (IL)-1β and IL-18, but had no affect the secretion of other cytokines such as IL-α, TNFα, IL-6 and IL-8 [2].

This product is also used in other models to illustrate the function of Caspase-1. Oral administration of VX-765 significantly reduced the severity of diseases and the inflammatory cytokines and chemokines secretion in the mouse model of rheumatoid arthritis and skin inflammation[1]. In addition, recent study demonstrated that VX-765 prevents CD4 T-cell pyroptotic death in a dose-dependent manner in HIV-infected lymphoid tissues [3].